# Intrinsic Asymmetry in Weak Acid Transmembrane Transporters

## TL;DR

This paper explores how asymmetry in transporters affects the direction of molecule movement across cell membranes, influencing biological processes like cancer progression.

## Contribution

The paper highlights experimentally confirmed cases of asymmetric transport and suggests overlooked biases in transport directionality.

## Key findings

- Loss of an extracellular domain increases lactate export from cancer cells by fourfold.
- Intrinsic asymmetry in transporters can shift transmembrane equilibrium by biased directionality.
- Molecular mechanisms of asymmetric transport are discussed with physiological implications.

## Abstract

Transmembrane facilitation of substrates by channels and secondary active transporters results in a defined steady-state concentration ratio across the membrane. Evidence is accumulating that asymmetry in the structural build of the transporters, or interaction with asymmetric partner proteins, can shift the position of the transmembrane equilibrium by biased transport directionality. For instance, the bacterial lactose transporter, LacY, and two amino acid transporters, i.e., the human excitatory amino acid carrier, EAAC1, and the yeast lysine permease, Lyp1, were reported to exhibit distinct transport kinetics in the inward and outward direction by protein-intrinsic properties. A recent example is transport modulation of human monocarboxylate transporters, MCT, by shedding of the extracellular domain of an ancillary protein, basigin. Loss of the domain selectively increases export of lactate from lung cancer cells by a factor of four, contributing to the Warburg effect and malignancy. Further, intrinsic properties of monocarboxylate transporters involving asymmetric affinities of substrate binding, or biased open probabilities were shown to generate preference for one transport direction. Here, we discuss molecular mechanisms and physiological contexts of asymmetric secondary active transmembrane transport. Focus is laid on experimentally established cases, and examples are given in which putative bias in transport directionality may have been overlooked.